Plk1, upregulated by HIF-2, mediates metastasis and drug resistance of clear cell renal cell carcinoma
Maeva Dufies, Annelies Verbiest, Lindsay S. Cooley, Papa Diogop Ndiaye, Xingkang He, Nicolas Nottet, Wilfried Souleyreau, Anaïs Hagege, Stéphanie Torrino, Julien Parola, Sandy Giuliano, Delphine Borchiellini, Renaud Schiappa, Baharia Mograbi, Jessica Zucman‐Rossi, Karim Bensalah, Alain Ravaud, Patrick Auberger, Andréas Bikfalvi, Emmanuel Chamorey, Nathalie Rioux-Leclercq, Nathalie M. Mazure, Benoit Beuselinck, Yihai Cao, Jean‐Christophe Bernhard, Damien Ambrosetti, Gilles Pagès
Abstract
Polo-like kinase 1 (Plk1) expression is inversely correlated with survival advantages in many cancers. However, molecular mechanisms that underlie Plk1 expression are poorly understood. Here, we uncover a hypoxia-regulated mechanism of Plk1-mediated cancer metastasis and drug resistance. We demonstrated that a HIF-2-dependent regulatory pathway drives Plk1 expression in clear cell renal cell carcinoma (ccRCC). Mechanistically, HIF-2 transcriptionally targets the hypoxia response element of the Plk1 promoter. In ccRCC patients, high expression of Plk1 was correlated to poor disease-free survival and overall survival. Loss-of-function of Plk1 in vivo markedly attenuated ccRCC growth and metastasis. High Plk1 expression conferred a resistant phenotype of ccRCC to targeted therapeutics such as sunitinib, in vitro, in vivo, and in metastatic ccRCC patients. Importantly, high Plk1 expression was defined in a subpopulation of ccRCC patients that are refractory to current therapies. Hence, we propose a therapeutic paradigm for improving outcomes of ccRCC patients.